Stabilized Formulation of Ivermectin Feed Premix with an Extended Shelf Life and Method of Making the Same

ABSTRACT

The invention relates to a stabilized premix feed or feed-like formulation that has an extended shelf life due to a decrease of the degradates of the active ingredient by controlling the amount of an already existing stabilizer in the formulation. The feed premix is used in the treatment or prophylaxis of parasites in mammals, in particular swine and horses. The invention further relates to a method to extend the shelf life of a stable premix feed or feed-like formulation for the treatment or prophylaxis of parasite infestation in swine and horses comprising controlling the amount of an already existing antioxidant or stabilizer in the formulation to decrease or to prevent the formation of acid/base catalyzed decomposition of the active ingredient.

RELATED APPLICATIONS

This application claims priority to Provisional Application U.S. Ser.No. 60/530,939 entitled “Stabilized Formulation of Ivermerctin FeedPremix in Swine and Horses with an Extended Shelf Life and Method ofMaking the Same” filed Dec. 23, 2003.

FIELD OF THE INVENTION

The present invention relates to increasing the shelf life of drugs,which include anthelmintics and antiparasitic agents, formulated aspremix feed or feed-like formulations. Particularly, the presentinvention provides for, inter alia, premix formulations and a method forincreasing the shelf-life of avermectin and milbemycin derivatives, suchas ivermectin, abamectin, emamectin, eprinomectin, doramectin,moxidectin, selamectin, and the like by controlling the amount of analready existing pharmaceutically or veterinary acceptable stabilizer inthe premix in an amount effective to adjust the pH range to betweenabout 4 to about 6 and therefore to decrease or to prevent the acid orbase catalyzed decomposition in the premix of the avermectin ormilbemycin compound, thereby extending the shelf life of the drug.

BACKGROUND OF THE INVENTION

Avermectin compounds are 16-membered macrocyclic lactones that arepotent anthelmintic and antiparasitic agents against a wide range ofinternal and external parasites. The compounds which belong to thisseries are either natural products or are semi-synthetic derivativesthereof. The natural product avermectins are disclosed in U.S. Pat. No.4,310,519 to Albers-Schonberg, et al., and the 22, 23-dihydro avermectincompounds are disclosed in Chabala, et al., U.S. Pat. No. 4,199,569. Fora general discussion of avermectins, which include a discussion of theiruses in humans and animals, see “Ivermectin and Abamectin,” W. C.Campbell, ed., Springer-Verlag, New York (1989). Furthermore, bioactiveagents such as avermectins or ivermectin can be used in combination withother bioactive agents; and, with respect to avermectins, ivermectin,and bioactive agent combinations, reference is made to Kitano, U.S. Pat.No. 4,468,390, Beuvry et al., U.S. Pat. No. 5,824,653, von Bittera etal., U.S. Pat. No. 4,283,400, European Patent Application 0 007 812 A1,published Jun. 2, 1980, U.K. Patent Specification 1 390 336, publishedApr. 9, 1975, European Patent Application 0002 916 A2, Ancare NewZealand Patent No. 237 086, Bayer New Zealand Patent 176193, publishedNov. 19, 1975, inter alia. These prior publications and all otherpublications cited herein are expressly incorporated by reference.

A number of antiparasitic and anthelmintic products on the marketcontain ivermectin as an active ingredient. For example, IVOMEC Premixmanufactured and sold by Merial is a free-flowing meal mixturecontaining 0.6% ivermectin for incorporation into animal feeding stuffs.It is indicated as an anthelmintic, insecticide and miticide againstparasites in pigs and horses (the trade name in horses is ZimecterinEZ). IVOMEC Premix offers unsurpassed efficacy against mange mites, liceand gastrointestinal worms of pigs. Mixed into the feed it may be usedin all classes of pigs and makes all round parasite control convenientand easy to apply. This compound treats a variety of parasites includinggastro-intestinal worms such as Ascaris suum, Hyostrongylus rubidus,Oesophagostomum spp., Strongyloides ransomi, Lungworms such asMetastrongylus spp., Lice such as Haematopinus suis, Mange mites such asSarcoptes scabiei var. suis. Ivomec premix for pigs given to pregnantsows before farrowing effectively controls transmission via the milk ofS. ransomi to piglets. Avermectins are susceptible to both acid and basecatalyzed decomposition. For example, the stability testing of IvomecSwine Premix indicated that the shelf life of the drug decreases overtime, possibly due to increase of ivermectin degradate resulted fromacid/base catalyzed decomposition.

Some studies have shown that by incorporating stabilizers into themedicated feed of some animals, said stabilizers can prevent or decreasethe degradation of the active ingredient and increase the shelf life ofsuch compounds. For example, U.S. Pat. No. 5,891,491 to Owens et al.have used substituted 1,2-dihydroquinoline compound, in the feed ofanimals in an amount sufficient to increase the shelf life of the feed.Also, U.S. Pat. No. 4,597,969 to Maxfield et al. have disclosed a methodof granulation involving polysaccharide gelling agents and metal saltsfor the stabilization of heat and or moisture sensitive drugs or foodsupplement such as efrotomycin, avermectins, milbemycins, moxidectin,and other drugs.

In light of the above, it is an object of the present invention toprovide for a stabilized premix comprising at least one avermectin ormilbemycin derivative for feed or feed-like formulations that exhibitimproved shelf life by decreasing or preventing the formation of thedegradates of the active ingredient. Moreover, it is an object of theinvention to provide for a method of decreasing or preventing theformulation of degradates in a premix comprising at least one avermectin or milbemycin derivative. These and other objects will becomeapparent from the following Description of the Invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the degradation products which occur when ivermectin issubjected to base catalyzed degradation.

FIG. 2 depicts the degradation products which occur when ivermectin issubjected to acid catalyzed degradation.

FIG. 3 depicts the reaction rate profile of the acid and base catalyzeddecomposition of ivermectin.

FIG. 4 depicts the decrease of ivermectin in the formulation over 18months when stored under 25° C./60% relative humidity storage condition.

FIG. 5 depicts the decrease of ivermectin in the formulation over 18months when stored under 30° C./60% relative humidity storage condition.

SUMMARY OF THE INVENTION

The invention provides for a stabilized premix feed or feed-likeformulation that has an extended shelf life due to a decrease orprevention of the degradates of the active ingredients by controllingthe amount of an already existing stabilizer in the formulation toadjust the pH of the premix to a range of about 4 to about 6. Morespecifically, the invention provides for, a stabilized premix feed orfeed-like formulation for the treatment or prophylaxis of parasiteinfestation in swine and horses with an extended shelf life.

This invention also provides for a method to extend the shelf life of anactive ingredient in a drug comprising controlling the amount of astabilizer in the formulation of said drug to decrease or to prevent theformation of acid/base catalyzed decomposition of said active ingredientby adjusting the pH of the premix formulation to a range of about 4 toabout 6

These and other embodiments are disclosed or are obvious from andencompassed by, the following Detailed Description.

In this disclosure and in the appended claims, terms such as“comprising” and “comprises” and the like, have the meanings as ascribedto them in U.S. Patent base law. The terms “comprises” and “comprising”are open-ended and allow for the inclusion of additional ingredients orsteps. Clearly, a stabilized premix which comprises an avermectin ormilbemycin derivative that comprises an increased amount of stabilizeras well as a method for stabilizing premixes, thereby increasing theirshelf life is a novel and basic feature of the invention. That theinvention performs as herein described is surprising, unexpected andnonobvious.

DETAILED DESCRIPTION OF THE INVENTION

A premix for an animal feed that exhibits an extended shelf-life whichcomprises:

-   -   a) a parasitically effective amount of at least one avermectin        or milbemycin;    -   b) a pharmaceutically acceptable excipient comprising:        -   i) a pharmaceutically acceptable surfactant;        -   ii) a pharmaceutically acceptable wax;        -   iii) a pharmaceutically acceptable antioxidant;        -   (iv) a pharmaceutically acceptable carrier vehicle wherein            said vehicle is selected from the group consisting of fine            corn cobs, corn meal, citrus meal, fermented residues,            ground oyster shells, wheat shorts, molasses solubles, bean            mill feed, soy grits, crushed limestone and dried grains;    -   c) a pharmaceutically acceptable amount of a pharmaceutically        acceptable stabilizer in an amount effective to adjust the pH of        the formulation to a range of about 4 about 6 to decrease or to        prevent the acid or base catalyzed decomposition in the premix        of the at least one avermectin or milbemycin compound; and    -   d) optionally, an effective amount of at least one insect growth        regulating compound.

A more preferred embodiment of the invention is a premix whichcomprises:

-   -   a) about 0.04 to about 5% (w/w) of at least one avermectin        compound;    -   b) a pharmaceutically acceptable excipient comprising:        -   i) about 5 to about 15% (w/w) of a surfactant wherein said            surfactant is selected from the group consisting of polyoxyl            40 hydrogenated castor oil, PEG-50 castor oil, PEG-60 corn            glyceride, PEG-60 almond oil, PEG-40 palm kernel oil, and            PEG-60 corn oil;        -   ii) about 5 to about 25% (w/w) of a wax wherein said wax is            selected from the group consisting of distilled            monoglycerides, glyceryl tribehenate, glyceryl trimyristate,            and hydrogenated coco-glycerides;        -   iii) about 0.1 to about 2% (w/w) of an antioxidant wherein            said antioxidant is selected from the group consisting of            butylated hydroxyanisole, butylated hydroxytoluene, ascorbic            acid, sodium metabisulphite, propyl gallate, sodium sulfite,            sodium thiosulphate, and a mixture thereof;        -   iv) about 60 to about 80% (w/w) of a pharmaceutically            acceptable carrier vehicle wherein said carrier vehicle is            selected from the group consisting of fine ground corn cobs,            crushed limestone, and dried grains,    -   c) a pharmaceutically acceptable amount of a pharmaceutically        acceptable stabilizer in an amount effective to adjust the pH of        the premix formulation to a range of about 4 to about 6 in order        to decrease the acid or base catalyzed decomposition of the at        least one avermectin or milbemycin compound said stabilizer is        selected from a group consisting of citric acid, gallic acid,        maleic acid, glycolic acid, thioglycolic acid, alginic acid and        a mixture thereof; and    -   d) optionally, an effective amount of at least one insect growth        regulating compound selected from the group consisting of        azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene,        methoprene, pyriproxyfen, tetrahydroazadirachtin, and        4-chloro-2-(2-chloro-2-methylpropyl)-5-(6-iodo-3-pyridylmethoxy)pyridizin-3(2H)-one        chlorfluazuron, cyromazine, diflubenzuron, fluazuron,        flucycloxuron, flufenoxuron, hexaflumuron, lufenuron,        tebufenozide, teflubenzuron, and triflumuron and a mixture        thereof.

Another embodiment of this invention provides for a method for extendingthe shelf life of a premix for an animal feed comprising at least onepharmaceutically active compound wherein said pharmaceutically activecompound is an avermectin or milbemycin compound said method comprisescontrolling the amount of a stabilizer in an amount effective to adjustthe pH of said premix formulation to a range of about 4 to about 6 inorder to decrease the acid or base catalyzed decomposition in the premixof the avermectin or milbemycin compound.

Avermectins and milbemycins are susceptible to both acid and basecatalyzed degradation. The macrocyclic lactone of all avermectins has atcarbon 13 an α-L-oleandrosyl-α-L-oleandrosyloxy substituent which is a2-deoxy sugar glycoside; and as such it is relatively sensitive to acidhydrolysis or alcoholysis. A solution of ivermectin in methanolcontaining a strong acid such as 1% sulfuric acid readily gives a goodyield of the aglycone after 16 to 24 hours at room temperature. Theseprocedures readily yield the monosaccharides of ivermectin andAvermectin B₁ and the aglycone of ivermectin.

Also, the two degradates, 2-epimer and the Δ^(2,3) isomer of avermectinand mylbemycins, are formed in the presence of a base. For example,decrease in ivermectin as the active ingredient in Premix formulationsis caused by formation of ivermectin degradate 2-epimer, which is aproduct of base catalyzed degradation in ivermectin. FIG. 1 illustratesthe two degradates, 2-epimer and the Δ^(2,3) isomer, that are formed inthe presence of a strong base. FIG. 2 illustrates the two degradates,monosaccharide and the aglycone, that are formed in the presence of astrong acid. FIG. 3 illustrates the reaction rate profile of acid andbase catalyzed hydrolysis of ivermectin.

The addition of an organic or inorganic base to the formulation couldprevent or decrease the amount of acid catalyzed degradates of theavermectins or milbemycins. Similarly, the addition of an organic orinorganic acid to the formulation could prevent or decrease the amountof base catalyzed degradates of avermectins. The modification in theamount of the organic acid already present in the excipient of thepresent formulation, is an object of this instant invention. Thus,advantageously, the invention provides for a stabilized premix feed orfeed-like formulation in the treatment or prophylaxis of parasites inmammals, and in particular swine and horses with an extended shelf life,by decreasing or preventing the degradation of the active ingredient dueto the modification of the amount of the already existing stabilizer inthe formulation that would adjust the pH of the premix formulation to arange of about 4 to about 6. In particular the modification in theamount of the existing stabilizer in the formulation comprises a smallincrease in the amount of such stabilizer in the formulation. That smallincreases could achieve these results is unexpected.

Stabilizers that decrease or prevent the acid or base catalyzeddecomposition of an avermectin or milbemycin in a premix include andcould be acids or bases. Organic acids and bases used in this instantinvention could be either anhydrous or hydrated (mono-, di-, tri-,tetra-, penta-, hexa, hepta, etc.). The term “acid” contemplates allpharmaceutically or veterinary acceptable inorganic or organic acids.Inorganic acids include mineral acids such as hydrohalic acids, such ashydrobromic and hydrochloric acids, sulfuric acids, phosphoric acids andnitric acids. Organic acids include all pharmaceutically orveterinary-acceptable aliphatic, alicyclic and aromatic carboxylicacids, dicarboxylic acids, tricarboxylic acids and fatty acids.Preferred acids are straight chain or branched, saturated or unsaturatedC₁-C₂₀ aliphatic carboxylic acids, which are optionally substituted byhalogen or by hydroxyl groups, or C₆-C₁₂ aromatic carboxylic acids.Examples of such acids are carbonic acid, formic acid, fumaric acid,acetic acid, propionic acid, isopropionic acid, valeric acid, α-hydroxyacids, such as glycolic acid, thioglycolic acid and lactic acid,chloroacetic acid, benzoic acid, methane sulfonic acid, and salicylicacid. Examples of dicarboxylic acids include oxalic acid, malic acid,succinic acid, tartaric acid and maleic acid. An example of atricarboxylic acid is citric acid. Fatty acids include allpharmaceutically or veterinary-acceptable saturated or unsaturatedaliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms.Examples include butyric acid, isobutyric acid, sec-butyric acid, lauricacid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenicacid, and phenylsteric acid. Other acids include gluconic acid,glycoheptonic acid and lactobionic acid, gallic acid, salicylic acid,malonic acid, ascorbic acid, isoascorbic acid, or a mixture thereof.

The term “base” contemplates all pharmaceutically or veterinaryacceptable inorganic or organic bases. Such bases include, for example,the alkali metal and alkaline earth metal salts, such as the lithium,sodium, potassium, magnesium or calcium salts. Organic bases include thecommon hydrocarbyl and heterocyclic amine salts, which include, forexample, the morpholine and piperidine salts.

Antioxidants used in this instant invention are well known in the artand particularly preferred antioxidants include but are not limited tobutylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid,sodium metabisulphite, propyl gallate, sodium thiosulphate or a mixturethereof. Preferably the antioxidants and/or stabilizers used in thisinvention are solubilized in suitable organic solvents well known in theart. Examples of organic solvents include but are limited to straightchain or branched alcohols such as methyl alcohol, ethyl alcohol, propylalcohol, butyl alcohol, isopropyl alcohol and the like, other solventsinclude but are not limited to benzylbenzoate, Crodamol, miglyol,ethylene glycol, propylene glycol, polyethylene glycol, glycerol,glycerol formal, N-methylpyrrolidone, sorbitol, pentaerythriol, and thelike.

The determination of an amount of stabilizer effective to decrease orprevent the acid or base catalyzed degradation that brings the pH rangeof the instant premix formulation to pH of about 4 to about 6 andthereby extends the shelf-life of the product by six to twenty-fourmonths, more preferably by nine to eighteen months and most preferablynine to twelve months, is made by increasing a small amount ofstabilizers in addition to that amount normally added in the art.Comparisons are made with respect to IVOMEC Premix. Preferred amounts ofthe stabilizer range from about 0.3 to about 1.5% (w/w), with about 0.3to about 1.2% (w/w) being more preferred. Most preferably the increasedamount of stabilizer is about 0.4 to about 0.5% (w/w).

This invention includes all avermectin derivatives known in the art.Especially preferred stabilized premix feed or feed-like formulationscomprising avermectin or milbemycin derivatives include but are notlimited to milbemycin, milbemycin oxime, abamectin, moxidectin,emamectin, eprinomectin, doramectin, selemectin and ivermectin.

In a most preferred embodiment the instant invention provides for astabilized premix feed or feed-like formulation for the treatment orprophylaxis of parasite infestation in swine and horses with an extendedshelf life comprising:

(a) 0.62% (w/w) of ivermectin,(b) a pharmaceutically or veterinary acceptable excipient consisting of:

-   -   (i) 8.00% (w/w) of polyoxyl 40 hydrogenated castor oil;    -   (ii) 20.80% (w/w) of distilled monoglycerides;    -   (iii) 0.13% (w/w) of butylated hydroxyanisole, propyl gallate,        and 0.02% (w/w) of anhydrous citric acid in 0.35% (w/w) of        propylene glycol    -   (iv) 69.6% (w/w) of fine ground corn cobs; and        (c) 0.48% (w/w) increase of anhydrous citric acid.

The term “excipient” contemplates all ingredients in the formulationthat are not part of the active ingredients. An excipient may includebut is not limited to solvents, waxes, antioxidants, stabilizers,solubilizers, liquid or solid vehicle carriers, anticaking agents andthe like.

In addition, the compounds of the present invention are administered viaan animal feedstuff, hence, they are intimately dispersed in the feed orused as a top dressing or in the form of pellets which may then be addedto the finished feed or optionally fed separately.

When the compounds described herein are administered as components ofthe feed of the animals, or dissolved or suspended in the drinkingwater, compositions are provided in which the active compounds areintimately dispersed in an inert carrier or diluent. Inert carrier meansone that will not react with the antiparasitic agent and one that may beadministered safely to animals. Preferably, a carrier for feedadministration is one that is, or may be, an ingredient of the animalration.

Suitable compositions include feed premixes or supplements in which theinstant compounds are present in relatively large amounts and which aresuitable for direct feeding to the animal or for addition to the feedeither directly or after an intermediate dilution or blending step.Typical carriers or diluents suitable for such compositions include, forexample, distillers' dried grains, corn meal, citrus meal, fermentationresidues, ground oyster shells, wheat shorts, molasses solubles, corncob meal, edible bean mill feed, soy grits, crushed limestone and thelike. The compounds of the present invention are intimately dispersedthroughout the carrier by methods such as grinding, stirring, milling ortumbling.

Examples of IGR compounds which may be used in the formulation of thepresent invention include compounds which mimic juvenile hormones andchitin-synthesis inhibitors. Preferred compounds that mimic juvenilehormones include azadirachtin, diofenolan, fenoxycarb, hydroprene,kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin,4-chloro-2-(2-chloro-2-methylpropyl)-5-(6-iodo-3-pyridylmethoxy)pyridizin-3(2H)-onepyridylmethoxy)pyridizin-3(2H)-one. Preferred and chitin-synthesisinhibitors include chlorfluazuron, cyromazine, diflubenzuron, fluazuron,flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, tebufenozide,teflubenzuron, triflumuron. These compounds are defined by theirinternational common name (The Pesticide Manual, 10^(th) edition, 1994,Ed. Clive Tomlin, Great Britain).

Chitin-synthesis inhibitors also include compounds such as1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-((trifluoromethyl))phenylurea,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy))phenylureaand 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylureaNovaluron (Isagro, Italian company) is also an example of an IGRcompound.

Preferred IGR compounds include methoprenes, pyriproxyfens, hydroprene,cyromazine, lufenuron,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea andnovaluron.

Antioxidant used in the present invention are well known in the art.Examples of antioxidants are but not limited to alpha tocopheral,ascorbic acid, ascrobyl palmitate, fumaric acid, malic acid, sodiumascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylatedhydroxy anisole), BHT (butylated hydroxy toluene) monothioglycerol andthe like.

The waxes in the instant invention are used to protect the activeingredient. Examples of waxes include distilled monoglycerids, glyceroltribehenate, glyceryl trimyristate and hydrogenated coco-glycerides.

A large number of surfactants of different degrees of hydrophobicity orhydrophilicity can be prepared by reaction of alcohols or polyalcoholswith a variety of natural and/or hydrogenated oils. Most commonly, theoils used are castor oil or hydrogenated castor oil, or an ediblevegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil,apricot kernel oil, soybean oil, or almond oil. Preferred alcoholsinclude glycerol, propylene glycol, ethylene glycol, polyethyleneglycol, sorbitol, and pentaerythritol. Among these alcohol-oiltransesterified surfactants, preferred hydrophilic surfactants arePEG-35 castor oil (Incrocas-35), PEG-40 hydrogenated castor oil(Cremophor RH 40), PEG-25 trioleate (TAGAT® TO), PEG-60 corn glycerides(Crovol M70), PEG-60 almond oil (Crovol A70), PEG-40 palm kernel oil(Crovol PK70), PEG-50 castor oil (Emalex C-50), PEG-50 hydrogenatedcastor oil (Emalex HC-50), PEG-8 caprylic/capric glycerides (Labrasol),and PEG-6 caprylic/capric glycerides (Sofligen 767). Preferredhydrophobic surfactants in this class include PEG-5 hydrogenated castoroil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6corn oil (Labrafil® M 2125 CS), PEG-6 almond oil (Labrafil® M 1966 CS),PEG-6 apricot kernel oil (Labrafil® M 1944 CS), PEG-6 olive oil(Labrafil® M 1980 CS), PEG-6 peanut oil (Labrafil(® M 1969 CS), PEG-6hydrogenated palm kernel oil (Labrafil® M 2130 BS), PEG-6 palm kerneloil (Labrafil® M 2130 CS), PEG-6 triolein (Labrafil® M 2735 CS),_PEG-8corn oil (Labrafil® WL 2609 BS), PEG-20 corn glycerides (Crovol M40),and PEG-20 almond glycerides (Crovol A40).

The following example is intended to illustrate the preparation of thecompositions of the invention but it is not to be construed as limitingthe scope thereof.

Example 1 Preparation of the Stabilized Premix Feed ComprisingIvermectin as an Active Ingredient

Polyoxyl 40 hydrogenated castor oil was heated to 75-85° C. Whilemaintaining this temperature, distilled monoglycerides was added to it.Once a homogeneous solution was achieved, BHA, n-propyl gallate,anhydrous citric acid and propylene glycol, were added to the mixture,followed by the addition of ivermectin. The temperature of the solutionwas then maintained at 75-85° C. In a suitable size mixer, fine groundcorncobs were charged and with continuous agitation the temperature wasraised to 75-85° C. The hot ivermectin solution was then transferred tothe heated corncobs, and the mixture was mixed until it becamehomogeneous. The vessel was then cooled with continuous agitation untilthe product temperature was below 40° C. Table I. shows the amount ofthe of the ingredients used to prepare the premix formulation of theinstant invention:

INGREDIENT COMPOSITION (w/w %) Ivermectin 0.62 Polyoxyl 40 Hydrogenated8.00 Castor Oil Distilled Monoglycerides 20.80 Butylated Hydroxyanisole0.10 Propyl Gallate 0.03 Anhydrous Citric Acid 0.02 Propylene Glycol0.35 Additional Anhydrous Citric Acid 0.48 Fine Ground Corn Cobs QS 100

Evaluation of stability studies for product without citric acid additionrevealed that Ivermectin Assay steadily decreased with time, when storedunder the VICH (International Cooperation on Harmonization of TechnicalRequirements for Registration of Veterinary Products) conditions. Datacollected after 9 months stability study for product with additionalamount of citric acid demonstrated better stability. Results are shownin Table II.

TABLE II Comparison of the stability of ivermectin at differenttemperature and relative humidity with and without addition of increasedcitric acid over a period of 9 month. Without Addition of IncreasedCitric Acid With Ivermectin Addition of Increased Citric Acid AssayIvermectin Assay (average) (average) 40° C./ Assay Time, 25° C./ Time,25° C./ 30° C./ 75% No. months 60% RH months 60% RH 60% RH RH 1 0 99.0 0101.4 101.4 101.4 1 98.7 — — — — 3 97.9 3 101.2 99.9 98.9 6 98.7 6 104.5100.6 96.2 9 104.3 100.2 — 2 0 100.8 0 100.9 100.9 100.9 3 99.8 3 101.6100.9 98.6 6 97.4 6 101.8 101.3 97.4 8 97.7 9 103.5 99.0 — 12 98.5 3 099.2 0 101.0 101.0 101.0 13 97.4 3 101.9 102.5 100.1 19 95.5 6 105.0103.1 98.4 24 93.0 9 100.1 101.3 — 29 92.4 4 0 98.3 13 97.2 19 95.7 2492.0 29 92.5 5 0 98.2 13 98.2 24 96.8

Table III compares the percentages of the ivermectin and ivermectindegradates over a 1 month period, under various storage conditions, whendifferent percentages of additional anhydrous citric acid are added tothe formulation that already contains 0.02% anhydrous citric acid.

TABLE III % of Assay added Storage No. Citric Acid Conditions Ivermectin% 2-epimer % Monosaccharide 1 0.28 5 C. 0.59 0 0.10 40 C./75% RH 0.550.17 0.13 50 C./amb 0.59 0.29 0.13 2 0.38 5 C. 0.55 0 0.13 40 C./75% RH0.53 0.15 0.17 50 C./amb 0.56 0.26 0.17 3 0.3 5 C. 0.57 0 0.17 40 C./75%RH 0.55 0.14 0.19 50 C./amb 0.58 0.24 0.23 4 0.48 5 C. 0.58 0 0.23 40C./75% RH 0.56 0.12 0.26 50 C./amb 0.59 0.22 0.30 5 0.73 5 C. 0.56 00.23 40 C./75% RH 0.54 0 0.31 50 C./amb 0.55 0.19 0.37 RH: relativehumidity amb: ambient temperature

TABLE IV Compares the percentages of the ivermectin (label claim) andivermectin degradates in the formulation up to 18 months in 3 differentassays where the total amount of citric acid in the formulation is about0.6%. ASSAY No. 1 Assay (Ivermectin) Ivermectin Related Substances95.0-105.0% of Max. 1.0% Label Claim Max. total 2.5% Max. Max. Max. 1.0%Unspecified Storage Time Label Claim H₂B_(1a) (delta) 2,3 + 1.0% 1.0%Mono- (each Max. 5% Total Condition (Months) 0.6% (w/w) H₄B_(1a) isomers2-epimer Aglycone saccharide individual) degradates 25° C./60% RH 3101.2-101.1 1.85 0 0.1 0.1 Max 0.3% 2.8 6 104.7-104.3 1.8 0 0 0.15 Max0.3% 2.95 9 101.1-101.4 1.8 0.1 0.2 0.2 Max 0.3% 2.7 12 98.3-99.4 1.80.15 0 0.15 Max 0.4% 3.0 18 100.2-99.9  1.8 0.2 0 0.2 Max. 0.5% 3.75 30°C./60% RH 3  99.3-100.4 1.8 0 0.15 0.1 Max 0.3% 2.7 6 101.0-100.2 1.80.2 0 0.2 Max 0.3% 2.7 9 100.6-99.7  1.9 0.3 0.2 0.2 Max 0.3% 2.7 1298.4-98.5 1.8 0.4 0 0.2 Max 0.3% 3.4 18 97.5-98.3 1.9 0.6 0 0.3 Max 0.5%4.7 40° C./75% RH 3 99.5-98.2 1.8 0.3 0.2 0.2 Max 0.3% 2.7 6 96.4-96.01.85 0.8 0 0.4 Max 0.3% 3.9 ASSAY No. 2 Assay (Ivermectin) IvermectinRelated Substances 95.0-105.0% of Max. 1.0% Label Claim Max. total 2.5%Max. Max. Max. 1.0% Unspecified Storage Time Label Claim H₂B_(1a)(delta) 2,3 + 1.0% 1.0% Mono- (each Max. 5% Total Condition (Month) 0.6%(w/w) H₄B_(1a) isomers 2-epimer Aglycone saccharide individual)degradates 25° C./60% RH 3 101.8-101.3 1.8 0 0 0.1 Max 0.35% 2.7 6101.8-101.8 1.8 0 0 0.15 Max 0.4% 3.2 9 103.3-103.6 1.8 0.1 0 0.15 Max0.35% 2.9 12 99.3-98.5 1.7 0.15 0.1 0.2 Max 0.55% 3.2 18 98.9-98.8 1.80.2 0 0.25 Max 0.5% 3.5 30° C./60% RH 3 101.3-100.5 1.8 0 0 0.15 Max0.35% 2.7 6 101.6-100.9 1.8 0.2 0 0.2 Max 0.35% 3.0 9 98.9-99.1 1.8 0.30.1 0.2 Max 0.35% 3.0 12 98.5-99.1 1.8 0.4 0 0.2 Max 0.5% 3.5 1897.7-98.2 0.6 0 0.3 Max 0.5% 4.7 40° C./75% RH 3 98.6-98.6 1.8 0.35 00.2 Max 0.3% 3.0 6 97.5-97.2 1.8 0.7 0 0.4 Max 0.4% 3.9 ASSAY No. 3Assay (Ivermectin) Ivermectin Related Substances 95.0-105.0% of Max.1.0% Label Claim Max. total 2.5% Max. Max. Max. 1.0% Unspecified StorageTime Label Claim H₂B_(1a) (delta) 2,3 + 1.0% 1.0% Mono- (each Max. 5%Total Condition (Month) 0.6% (w/w) H₄B_(1a) isomers 2-epimer Aglyconesaccharide individual) degradates 25° C./60% RH 3 102.0-101.8 1.8 0 00.1 Max 0.3% 2.7 6 105.0-105.3 1.8 0 0 0.15 Max 0.3% 3.0 9 100.7-99.5 1.85 0 0 0.2 Max 0.3% 2.7 12 101.4-102.1 1.8 0.1 0.1 0.15 Max 0.6% 3.218 99.9-99.9 1.8 0.2 0 0.2 Max 0.5% 3.5 30° C./60% RH 3 103.1-101.8 1.80 0 0.1 Max 0.3% 3.0 6 102.6-103.6 1.8 0.1 0 0.2 Max 0.3% 3.0 9101.5-101.1 1.8 0.2 0.1 0.2 Max 0.3% 2.7 12  99.9-100.6 1.8 0.3 0.1 0.2Max 0.5% 3.5 18 98.9-99.4 1.9 0.5 0 0.3 Max 0.5% 4.7 40° C./75% RH 3 99.1-101.0 1.9 0.3 0 0.2 Max 0.3% 3.0 6 98.7-98.1 1.9 0.6 0 0.4 Max0.3% 4.0

These results confirm the improved stability profile of the instantinvention with an average ivermectin assay result well above the 95%specification limit after 18 months of storage at both 25° C./60% RH and30° C./60% RH. In addition the rate of degradation of ivermectin isbetter controlled with a total amount of degradates below the 5%specification limit which is the maximum level of degradates allowed forthis instant invention and is the currently approved specification atshelf-life.

By applying a Linear Regression Model to the data shown in Table IV. andFIGS. 4 and 5, one obtains the relationship between Ivermectin content(Y) and the shelf-life of the drug (X) expressed in Months as follows:Y=101.4714+(−9.789569E-02)X at 25° C./60% RH storage condition andY=101.4181+(−0.1805759)X at 30° C./60% RH storage conditionrespectively. The graphs in FIGS. 4 and 5 show that the content ofivermectin stays well above the 95% limit which is the currentlyapproved specification at shelf-life even after 24 months.

The above description of the invention is intended to be illustrativeand not limiting. Various changes or modifications in the embodimentsdescribed herein may occur to those skilled in the art. These can bemade without departing from the scope and spirit of the invention.

1. A premix for an animal feed that exhibits an extended shelf-lifewhich comprises: a) a parasitically effective amount of at least oneavermectin or milbemycin; b) a pharmaceutically acceptable excipientcomprising: i) a pharmaceutically acceptable surfactant; ii) apharmaceutically acceptable wax; iii) a pharmaceutically acceptableantioxidant; iv) a pharmaceutically acceptable carrier vehicle whereinsaid vehicle is selected from the group consisting of fine corn cobs,corn meal, citrus meal, fermentation residues, ground oyster shells,wheat shorts, molasses solubles, bean mill feed, soy grits, crushedlimestone and dried grains; c) a pharmaceutically acceptable amount of apharmaceutically acceptable stabilizer in an amount effective to adjustthe pH of the premix formulation to a range of about 4 to about 6 andthereby to decrease or to prevent the acid or base catalyzeddecomposition in the premix of the at least one avermectin or milbemycincompound; and d) optionally, an effective amount of at least one insectgrowth regulating compound.
 2. The premix according to claim 1, whereinthe avermectin or milbemycin is selected from the group consisting ofivermectin, abamectin, emamectin, eprinomectin, doramectin, moxidectin,milbemycin oxime and selamectin.
 3. The premix according to claim 1,wherein the insect growth regulating compound is one that mimicsjuvenile hormones.
 4. The premix according to claim 3, wherein theinsect growth regulating compound is selected from the group consistingof azadirchtin, diofenolan, fenoxycarb, hydroprene, kinoprene,methoprene, pyriproxyfen, tetrahydroazadirachtin, and4-chloro-2-(2-chloro-2-methylpropyl)-5-(6-iodo-3-pyridylmethoxy)pyridizin-3(2H)-one.5. The premix according to claim 1 wherein the insect growth regulatingcompound is one that inhibits chitin synthesis.
 6. The premix accordingto claim 3, wherein the insect growth regulating compound is selectedfrom the group consisting of chlorfluazuron, cyromazine, diflubenzuron,fluazuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron,tebufenozide, teflubenzuron, and triflumuron.
 7. The premix according toclaim 1 wherein the insect growth regulating compound is selected fromthe group consisting of methoprenes, pyriproxyfens, hydrofene,cyromazine, lufenuron,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea,novaluron and a mixture thereof.
 8. The premix formulation according toclaim 1 wherein the pH of the premix is about
 5. 9. (canceled) 10.(canceled)
 11. The premix formulation according to claim 1 wherein thestabilizer is selected from a group consisting of: anhydrous citricacid, glycolic acid, thioglycolic acid, gallic acid, maleic acid, and amixture thereof.
 12. The premix formulation according to claim 11wherein the stabilizer is anhydrous citric acid.
 13. The premixaccording to claim 1 which comprises: a) about 0.04 to about 5% (w/w) ofat least one avermectin compound; b) a pharmaceutically acceptableexcipient comprising: i) about 5 to about 15% (w/w) of a surfactantwherein said surfactant is selected from the group consisting ofpolyoxyl 40 hydrogenated castor oil, PEG-50 castor oil, PEG-60 cornglyceride, PEG-60 almond oil, PEG-40 palm kernel oil, and PEG-60 cornoil; ii) about 5 to about 25% (w/w) of a wax wherein said wax isselected from the group consisting of distilled monoglycerides, glyceryltribehenate, glyceryl trimyristate, and hydrogenated coco-glycerides;iii) about 0.1 to about 2% (w/w) of at least one antioxidant, whereinsaid at least one antioxidant is selected from the group consisting ofbutylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid,sodium metabisulphite, propyl gallate, sodium thiosulphate, and amixture thereof; iv) about 60 to about 80% (w/w) of a pharmaceuticallyacceptable carrier vehicle wherein said carrier vehicle is selected fromthe group consisting of fine ground corn cobs, crushed limestone, anddried grains; c) a pharmaceutically acceptable amount of apharmaceutically acceptable stabilizer in an amount effective to adjustthe pH of the premix to a range of about 4 to about 6 in order todecrease the acid or base catalyzed decomposition of the at least oneavermectin or milbemycin compound, and; d) optionally, a effectiveamount of at least one insect growth regulating compound selected fromthe group consisting of methopenes, pyriproxyfens, hydrofene,cyromazine, lufenuron,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea,novaluron and a mixture thereof.
 14. The premix according to claim 1,the amount of the added stabilizer is between about 0.3 to about 1.2%(w/w).
 15. The premix according to claim 1 wherein the amount of theadded stabilizer is about 0.4 to about 0.5% (w/w).
 16. The premixaccording to claim 1 wherein the animal feed is swine feed or horsefeed.
 17. A method for extending the shelf life of a premix for ananimal feed comprising at least one pharmaceutically active compoundwherein said pharmaceutically active compound is an avermectin ormilbemycin compound; comprising increasing the amount of the alreadyexisting stabilizer in an amount effective to adjust the pH of thepremix to a range of about 4 to about 6 to decrease the acid or basecatalyzed decomposition in the premix of the avermectin or milbemycincompound.
 18. The method according to claim 17, wherein the stabilizeris anhydrous citric acid and the at least one avermectin or milbemycinis ivermectin.
 19. The method according to claim 17, wherein the amountof stabilizer is about 0.3 to about 1.2% (w/w).
 20. The method accordingto claim 17, wherein the amount of stabilizer is about 0.4 to about 0.5%(w/w).
 21. The method according to claim 17 wherein the shelf life isextended from 6 to 24 months.
 22. (canceled)
 23. The method according toclaim 17, wherein the animal feed is swine feed or animal feed.